Rapid Evolution of Major Histocompatibility Complex Class I Genes in Primates Generates New Disease Alleles in Humans Via Hitchhiking Diversity

By Shiina, Takashi; Ota, Masao et al. | Genetics, July 2006 | Go to article overview

Rapid Evolution of Major Histocompatibility Complex Class I Genes in Primates Generates New Disease Alleles in Humans Via Hitchhiking Diversity


Shiina, Takashi, Ota, Masao, Shimizu, Sayoko, Katsuyama, Yoshihiko, et al., Genetics


ABSTRACT

A plausible explanation for many MHC-linked diseases is lacking. Sequencing of the MHC class I region (coding units or full contigs) in several human and nonhuman primate haplotypes allowed an analysis of single nucleotide variations (SNV) across this entire segment. This diversity was not evenly distributed. It was rather concentrated within two gene-rich clusters. These were each centered, but importantly not limited to, the antigen-presenting HLA-A and HLA-B/-C loci. Rapid evolution of MHC-I alleles, as evidenced by an unusually high number of haplotype-specific (hs) and hypervariable (hv) (which could not be traced to a single species or haplotype) SNVs within the classical MHC-I, seems to have not only hitchhiked alleles within nearby genes, but also hitchhiked deleterious mutations in these same unrelated loci. The overrepresentation of a fraction of these hvSNV (hv1SNV) along with hsSNV, as compared to those that appear to have been maintained throughout primate evolution (trans-species diversity; tsSNV; included within hv2SNV) tends to establish that the majority of the MHC polymorphism is de novo (species specific). This is most likely reminiscent of the fact that these hsSNV and hv1SNV have been selected in adaptation to the constantly evolving microbial antigenic repertoire.

THE human major histocompatibility complex (MHC; also known as HLA), a minute (4-Mb) segment of the genome, harbors the full range of challenges awaiting a genome-scale search for predisposing loci to complex disorders (HIRSCHHORN and DALY 2005). The MHC is characterized by a set of highly polymorphic (>1700 alleles) antigen-presenting HLA class I and II genes, embedded within well over 230 loci, collectively associated with >100 pathologies (HLA 2004). Remarkably, recent genomewide scans have shown that, for a majority of these diseases, the MHC remains the first and foremost genetic component to pathogenesis (ONENGUT-GUMUSCU and CONCANNON 2002). However, to date, with few exceptions (see below), it has been extremely difficult to identify genuine mutations/ polymorphisms at the origin of the observed associations. This in large part has been due to two facts. First, the lack (until recently) of anonymous markers (that is, in addition to the highly polymorphic MHC genes themselves), i.e., microsatellites and SNPs. Second, the presence of a strong degree of linkage disequilibrium across the region, which yields to the existence of extended haplotypes (CEPPELLINI et al. 1955), a well-established fact that has gained recent momentum, given the initiation of the international HapMap project (GABRIEL et al. 2002). To alleviate both these hurdles, it is necessary, following the report of the first human MHC sequence (MHC SEQUENCING CONSORTIUM 1999), to sequence in fine significant numbers of single MHC haplotypes. As medically important as the identification of the molecular basis of HLA-disease association is, a more fundamental question is, why are so many diseases linked to the MHC in the first place? The simple answer resides "somewhere" in the fact that MHC is polymorphic, which immediately raises a second question: Through which mechanism(s) has this level of diversity been created and maintained within the MHC? The answer to the second question (and by inference to the first) has occupied the field for the last 30 years. Here we aim to capitalize on sequence analysis of both human and nonhuman primate MHC haplotypes to answer these important questions.

MATERIALS AND METHODS

Human: Cell lines: Genomic DNA was extracted from the HLA homozygous AKIBA (HLA-A24, -B52, -DR15 haplotype, IHW number 9286), LKT3 (HLA-A24, -B54, -DR4 haplotype, IHW number 9107), and JPKO (HLA-A33, -B44, -DR13 haplotype) cell lines (kindly provided by F. Numano, T. Kaneko, and Y. Ishikawa) (http://www.ecacc.org.uk/), representing the highest (8.2%), fourth highest (2.3%), and second highest (5.2%) population frequency, respectively, within the Japanese population (haplotype frequency data of the 11th International Histocompatibility Workshop; http://www. …

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